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GAS6 Inhibits Granulocyte Adhesion to Endothelial Cells
Gian Carlo Avanzi,
Margherita Gallicchio,
Flavia Bottarel,
Loretta Gammaitoni,
Giuliana Cavalloni,
Donatella Buonfiglio,
Manuela Bragardo,
Giorgio Bellomo,
Emanuele Albano,
Roberto Fantozzi,
Giovanni Garbarino,
Brian Varnum,
Massimo Aglietta,
Giuseppe Saglio,
Umberto Dianzani, and
Chiara Dianzani
From the Dipartimento di Scienze Mediche, Dipartimento di Scienze
Biomediche ed Oncologia Umana, Dipartimento di Anatomia, Farmacologia e
Medicina Legale and Dipartimento di Scienze Biomediche ed Oncologia
Umana and Divisione Universitaria di Ematologia ed Oncologia,
Università di Torino, Torino, Italy; and Amgen Inc, Thousand
Oaks, CA.
GAS6 is a ligand for the tyrosine kinase receptors Rse, Axl, and
Mer, but its function is poorly understood. Previous studies reported
that both GAS6 and Axl are expressed by vascular endothelial cells
(EC), which play a key role in leukocyte extravasation into tissues
during inflammation through adhesive interactions with these cells. The
aim of this work was to evaluate the GAS6 effect on the adhesive
function of EC. Treatment of EC with GAS6 significantly inhibited
adhesion of polymorphonuclear cells (PMN) induced by phorbol
12-myristate 13-acetate (PMA), platelet-activating factor (PAF), thrombin, interleukin-1 (IL-1) and tumor
necrosis factor- (TNF-), but not that induced by FMLP and IL-8.
GAS6 did not affect adhesion to resting EC. Titration experiments
showed that high concentrations of GAS6 were needed to inhibit PMN
adhesion and that inhibition was dose-dependent at the concentration
range of 0.1 to 1 µg/mL. One possibility was that high concentrations were needed to overwhelm the effect of endogenous GAS6 produced by EC.
In line with this possibility, treatment of resting EC with soluble Axl
significantly potentiated PMN adhesion. Analysis of localization of
GAS6 by confocal microscopy and cytofluorimetric analysis showed that
it is concentrated along the plasma membrane in resting EC and
treatment with PAF induces depletion and/or redistribution of
the molecule. These data suggest that GAS6 functions as a physiologic
antiinflammatory agent produced by resting EC and depleted when
proinflammatory stimuli turn on the proadhesive machinery of EC.
Blood, Vol. 91 No. 7 (April 1), 1998:
pp. 2334-2340
© 1998 by The American Society of Hematology.
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